TL1A (TNFSF15) Regulates the Development of Chronic Colitis by Modulating Both T-Helper 1 and T-Helper 17 Activation

Background & Aims: TL1A is a tumor necrosis factor-like molecule that mediates a strong costimulation of T-helper (TH) 1 cells. Expression of TL1A is increased in the mucosa of Crohn's disease patients and murine models of ileitis. The aim of this study was to determine the possible role of TL1A in chronic intestinal inflammation. Methods:We used dextran sodium sulfate (DSS)-induced chronic colitis to investigate the effects of TL1A on the development of colitis. The cytokine profile in the gut-associated lymphoid tissue (GALT) was measured. Neutralizing anti-TL1A antibodies were injected intraperitoneally into DSS-induced chronic colitis and G protein αi2−/− T-cell transfer colitis models. Severity of colitis was evaluated by body weight, colon length, histology, and cytokine production. Results:DSS-induced chronic colitis was characterized by the infiltration of CD4+ T cells. TL1A, death receptor 3, interferon (IFN)-γ, and interleukin (IL)-17 were increased significantly in GALT of DSS-treated mice. TL1A up-regulated both IFN-γ production from TH1 cells and IL-17 production from TH17 cells in GALT CD4+ T cells. Furthermore, IFN-γ and IL-17 production from CD4+ T cells, induced by IL-12 and IL-23 respectively, was enhanced synergistically by combination with TL1A. Anti-TL1A antibody prevented chronic colitis and attenuated established colitis by down-regulation of both TH1 and TH17 activation. Conclusions:Our results reveal that TL1A is an important modulator in the development of chronic mucosal inflammation by enhancing TH1 and TH17 effector functions. The central role of TL1A represents an attractive, novel therapeutic target for the treatment of Crohn's disease patients.